Describe full agonists, partial agonists and inverse agonists in terms of constitutive activity of a receptor

The Two-state Receptor Model

A receptor must exist in at least two conformations, active (Ra) and inactive (Ri).
• The receptor is believed to exist in two interchangeable states, Ra and Ri, which are in equilibrium, such that no signal is generated in the resting state.
• The extent, to which this equilibrium is distributed, is determined by the relative affinity of the drug for the two conformations.
• If a drug has a higher affinity for the Ra conformation and binds with it, will drive (shift) the equilibrium to the active state and thereby activate the receptor, the Ra predominates and a response is generated. Such a drug will be an agonist.
• A full agonist is very selective for the active state, so that, at a saturating concentration, it will drive the receptor completely to the active state.
• If a different but structurally similar compound binds to the same receptor but with slightly greater affinity for Ra than for Ri, the equilibrium is only modesty shifted towards Ra and the magnitude of effect may be less (submaximal) even at saturating concentrations. A drug that exhibits such intermediate effectiveness, is called Partial Agonist.
• A drug that binds with equal affinity to either conformation, will not alter the activation equilibrium and will act as a competitive antagonist. A partial agonist also can act as an antagonist.
• The inverse agonist has a high affinity for Ri state, therefore it can produce an opposite response to that of an agonist.

Many antagonists in use now a days are now believed to be ‘inverse agonists’ including some beta blockers, anti-histamines, atypical anti-psychotics.

For more details and similar explanations see my book

‘Nauman’s Textbook of Pharmacology’ 3rd Edition

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